Stent coating

ABSTRACT

A stent comprising a coating layer is disclosed. The coating layer has a hydrophobic component and a hydrophilic component, wherein a region of the coating layer on or about the outermost surface of the coating layer has a higher content or concentration of the hydrophilic component than the hydrophobic component.

CROSS REFERENCE

This application is a continuation-in-part of application Ser. No.10/375,620, filed on Feb. 26, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to coatings for drug delivery devices, suchas drug eluting vascular stents, and methods for producing the same.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer.

Local administration of therapeutic agents via stents has shown somefavorable results in reducing restenosis. However, the properties ofstent coatings can be improved. For example, when the outermost layer ofthe coating comprises a blend of hydrophobic and hydrophilic polymers,the hydrophobic polymers tend to bloom to coating-air interface. Yet, inmany applications it is highly desirable to have hydrophilic polymersevolve at the coating-air interface to provide the stent coating withbetter blood compatibility, biological activity and non-foulingproperties. Accordingly, the present invention discloses such improvedstent coatings and methods for fabricating thereof.

SUMMARY

A stent comprising a coating layer is disclosed, the coating layerhaving a hydrophobic component and a hydrophilic component, wherein aregion of the coating layer on or about the outermost surface of thecoating layer has a higher content or concentration of the hydrophiliccomponent than the hydrophobic component and wherein the hydrophiliccomponent has a solubility parameter higher than about 8.5(cal/cm³)^(1/2). The hydrophobic and hydrophilic components can be inblended format in the coating layer. The hydrophobic and hydrophiliccomponents can be bonded in the coating layer. The hydrophobic andhydrophilic components can be an interpenetrating polymer network. Insome embodiments, the hydrophobic component has a solubility parameterless than about 11.5 (cal/cm³)^(1/2). The coating layer can include oneor a combination of a primer layer, a reservoir layer including a drugand a topcoat layer.

DETAILED DESCRIPTION

A coating or coating layer for an implantable medical device, such as astent, according to one embodiment of the present invention, can includea drug-polymer layer (also referred to as “reservoir” or “reservoirlayer”) or alternatively a polymer free drug layer, an optional primerlayer and an optional topcoat layer. The drug-polymer layer serves as areservoir for the drug. The reservoir layer or the polymer free druglayer can be applied directly onto the stent surface. The optionaltopcoat layer, which can be essentially free from any drugs, serves as arate limiting membrane which helps to control the rate of release of thedrug. The optional primer layer can be applied on the stent surface toimprove the adhesion of the drug-polymer layer or the polymer free druglayer to the stent.

The reservoir layer and the optional primer and topcoat layers of thecoating can be formed on the stent by dissolving a polymer or a blend ofpolymers in a solvent, or a mixture of solvents, and applying theresulting polymer solution on the stent by spraying or immersing thestent in the solution. To incorporate a drug into the reservoir layer,the drug in a form of a solution can be combined with the polymersolution. Alternatively, to fabricate a polymer free drug layer, thedrug can be dissolved in a suitable solvent or mixture of solvents, andthe resulting drug solution can be applied on the stent by spraying orimmersing the stent in the drug solution.

Instead of introducing the drug in a solution, the drug can beintroduced as a colloid system, such as a suspension in an appropriatesolvent phase. To make the suspension, the drug can be dispersed in thesolvent phase using conventional techniques used in colloid chemistry.Depending on a variety of factors, e.g., the nature of the drug, thosehaving ordinary skill in the art will select the suitable solvent toform the solvent phase of the suspension, as well as the quantity of thedrug to be dispersed in the solvent phase. The suspension can be mixedwith a polymer solution and the mixture can be applied on the stent asdescribed above. Alternatively; the drug suspension can be applied onthe stent without being mixed with the polymer solution.

The outermost layer of the stent coating can be either the topcoat layeror the reservoir layer (if the optional topcoat layer is not used). Insome embodiments, the outermost layer of the stent coating is comprisedof a blend of polymers, the blend to include one or more hydrophilicpolymers and one or more hydrophobic polymers. In some embodiments, themass ratio between the hydrophilic and hydrophobic polymers in thecoating or the outermost layer of the coating can be typically betweenabout 1:100 and 1:9.

Generally, hydrophobicity of a polymer or component in the coating canbe gauged using the Hildebrand solubility parameter δ. The term“Hildebrand solubility parameter” refers to a parameter measuring thecohesion of a substance. The δ parameter is determined as follows:δ=(ΔE/V)^(1/2)where

-   δ is the solubility parameter, (cal/cm³)^(1/2);-   ΔE is the energy of vaporization, cal/mole; and-   V is the molar volume, cm³/mole.

Whichever polymer or component in the combination, mixture, blend,bonding or conjugation has the lower δ value as compared to the δ valueof the other component is designated as hydrophobic, and the componentwith the higher δ value is designated as hydrophilic. If more than twocomponents or polymers are used such as in the combined, mixed, blended,bonded or conjugated chemical, then each can be ranked in order of its δvalue. For the practice of the present invention, the value of δ of aparticular component or polymer is inconsequential for classifying it ashydrophobic or hydrophilic so long as the difference in the δ values ofthe two components or polymers is sufficient to allow the hydrophilicpart or unit to migrate or bloom to the surface as described below. Insome embodiment, the δ value defining the boundary betweenhydrophobicity and hydrophilicity can be about 8.0 (cal/cm³)^(1/2)(i.e., the hydrophilic component is above about 8.0 (cal/cm³)^(1/2). Insome embodiments, the hydrophilic component can have a value above about8.5, 9.0, 9.5, 10.0, 10.5, 11.0 or 11.5(cal/cm³)^(1/2). In someembodiments, the hydrophobic component can be below about 8.5, 9.0, 9.5,10.0, 10.5, 11.0 or 11.5(cal/cm³)^(1/2). In some embodiments thehydrophilic component can be a non-fouling component, bioactivecomponent and/or a biobeneficial component in addition to or in lieu ofhaving the Hildebrand value(s) described above. In one embodiment,non-fouling is defined as not capable of adsorbing or attractingproteins, or adsorbing or attracting only a minimal amount of proteins,or less proteins than a compound not having a non-fouling moiety. A“bioactive component” can be a component or moiety that can be combinedwith a polymer and provides a therapeutic effect, a prophylactic effect,both a therapeutic and a prophylactic effect, or other biologicallyactive effect within a subject. Moreover, the bioactive component mayremain linked to a portion of the polymer or be released from thepolymer. A “biobeneficial component” can be a substance that can becombined with a polymer and provide a biological benefit within asubject without necessarily being released from the polymer.

Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a polymer thatcan be utilized as a hydrophobic component to fabricate the reservoirlayer or the topcoat layer. EVAL can be used to make the optional primerlayer as well. EVAL is a product of hydrolysis of ethylene-vinyl acetatecopolymers and has the general formula —[CH₂—CH₂]_(m)—[CH₂—CH(OH)]_(n)—.EVAL may also include a terpolymer having up to about 5 molar % of unitsderived from styrene, propylene and other suitable unsaturated monomers.A brand of copolymer of ethylene and vinyl alcohol distributedcommercially under the trade name EVAL by Aldrich Chemical Co. ofMilwaukee, Wis., can be used.

Other examples of hydrophobic and hydrophilic components that can beused include polyacrylates, such as poly(butyl methacrylate), poly(ethylmethacrylate), and poly(ethyl methacrylate-co-butyl methacrylate), andfluorinated polymers and/or copolymers, such as poly(vinylidenefluoride) and poly(vinylidene fluoride-co-hexafluoro propene),poly(vinyl pyrrolidone), poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters), polyalkyleneoxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen,cellulose, starch, collagen and hyaluronic acid), polyurethanes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, vinyl halide polymers and copolymers(such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methylether), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose.

Representative examples of some solvents suitable for making the stentcoatings include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide(DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, acetone,i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether,methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane. Somesolvent mixtures can be used as well. Representative examples of themixtures include:

-   -   (1) DMAC and methanol (e.g., a 50:50 by mass mixture);    -   (2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass        mixture);    -   (3) i-propanol and DMAC (e.g., 80:20, 50:50, or 20:80 by mass        mixtures);    -   (4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by        mass mixtures);    -   (5) acetone and xylene (e.g. a 50:50 by mass mixture);    -   (6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40 by        mass mixture); and    -   (7) 1,1,2-trichloroethane and chloroform (e.g., a 80:20 by mass        mixture).

FLUX REMOVER AMS is trade name of a solvent manufactured by Tech Spray,Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance of methanol,with trace amounts of nitromethane. Those having ordinary skill in theart will select the solvent or a mixture of solvents suitable for aparticular polymer being dissolved.

Following the formation of the stent coating comprising hydrophobic andhydrophilic polymers or components, the coating can be treated to enrichthe surface with the hydrophilic polymer(s) or component(s). The coatingcan be dry, i.e., solvent free or wet, i.e., any amount of solventduring the treatment process. The stent coating referred to herein canbe the reservoir layer, the topcoat layer, an outermost layer or acombination of any layers including the primer layer. As a result ofpromotion of the hydrophilic substance, a region of the coating layer onor about the outermost surface of the coating layer will have a higheramount, content or concentration of the hydrophilic component than thehydrophobic component. The region of the coating closer to the stentsurface will have a higher amount, content or concentration of thehydrophilic component.

According to one method of the post-coating treatment, the coated stentcan be exposed to the environment of a humidifying chamber. The lengthof such treatment can be between about 12 hours and 28 hours, forexample, about 24 hours, at a temperature of about 40° C. to about 80°C., more narrowly, between about 45° C. and about 60° C., for example,about 50° C. and relative humidity of about 90% to about 100%. Anycommercially available humidifying chamber can be used. As a result ofthe exposure of the stent to high humidity levels at elevatedtemperatures, water is expected to be deposited on the surface of thestent coating. Water will gradually extract the hydrophilic polymer tothe coating surface leading to migration of the hydrophilic polymer andits blooming to the coating-air interface.

According to another method of the post-coating treatment, the coatedstent can be physically placed on a film of a hydrogel, for example, apoly(vinyl alcohol) hydrogel, and gently rolled back and forth a numberof times covering the entire circumference of the stent. For example,the coated stent can be rolled in the described fashion between 5 and 10times, while a pressure of between about 1 atm and 3 atm is applied tothe stent when it is being rolled. The physical contact between the filmof the hydrogel and the stent coating can alter the coating-airinterface, resulting in extraction of the hydrophilic polymer and itsblooming to the coating-air interface.

According to yet another method of the post-coating treatment, thecoated stent can be cooled or chilled at a temperature below ambienttemperature. In some embodiments between about 4° C. and about −20° C.for a period of time between about 30 minutes and about 2 hours.Following the cooling process, the stent can be either exposed toambient air for about 24 hours, or treated in the humidifying chamber asdescribed above. This procedure is expected to lead to condensation ofwater on the surface of the coating, resulting in extraction of thehydrophilic polymer and its blooming to the coating-air interface.

Optionally, any combination of the three methods of the post-coatingtreatment described above can be used, if desired. As another option,following the post-coating treatment, the coated stent can be heated toa temperature which is about equal to the glass transition temperature(T_(g)) of the hydrophobic component of the coating.

In another embodiment, instead of a blend of a hydrophobic andhydrophilic polymer, an interpenetrating polymer network (IPN) can beused to make the outermost layer of the stent coating, the IPN includesat least one hydrophobic component and at least one hydrophiliccomponent. For the purposes of the present invention, the definition ofthe IPN used by the International Union of Pure and Applied Chemistry(IUPAC) is adopted. The IUPAC describes the IPN as a polymer comprisingtwo or more networks which are at least partially interlaced on amolecular scale, to form both chemical and physical bonds between thenetworks. The networks of an IPN cannot be separated unless chemicalbonds are broken. In other words, an IPN structure represents two ormore polymer networks that are partially chemically cross-linked andpartially physically entangled. One example of an IPN that can be usedis a surface hydrogel.

One example of a product that can be used for forming the IPN is aPEG-based unsaturated product, for example, pre-polymer of PEG-acrylateor PEG-methacrylate having a general formulaCH₂═CX—COO—[CH₂—CH₂—O]_(n)—H, where X is hydrogen (acrylates) or methyl(methacrylates). The molecular weight of PEG-acrylate or methacrylatecan be within a range of about 10,000 to 100,00 Daltons. PEG-acrylate orPEG-methacrylate prepolymer can be applied on the surface of thedrug-polymer layer or topcoat layer and cured, for example, using aradical initiator which is activated by UV radiation (UV initiators),light (light initiators), or heat (thermal initiators). Examples ofappropriate initiators include acetophenone,2,2-dimethoxy-2-phenol-acetophenone (UV initiators), camproquinone,ethyl-4-N,N,-dimethyl aminobenzoate (light initiators), and benzoylperoxide (thermal initiator). As a result of the curing process,PEG-acrylate or PEG-methacrylate will partially cross-link and partiallyphysically entangle with the polymer of the underlying drug-polymerlayer thus forming the outermost coat layer which includes an IPN.PEG-acrylate or PEG-methacrylate is intended to broadly includepoly(ethylene glycol)-diacrylate (PEG-diacrylate) and poly(ethyleneglycol)-dimethacrylate (PEG-dimethacrylate). PEG-acrylate orPEG-methacrylate and PEG-diacrylate or PEG-dimethacrylate can beoptionally terminated, for example, with stearic acid, to formPEG-acrylate-stearate or PEG-methacrylate-stearate, respectively.

Examples of other products that can be used for forming the IPN includesuch unsaturated reactive products as N-vinylpyrrolidone, heparin andits derivatives, hyaluronic acid and its derivatives, somehydrogel-forming products such as poly(butyleneterephthalate-co-ethyleneglycol) (PBT-PEG), and mixtures of any of these products with each otheror with PEG-acrylate or PEG-methacrylate. A type of PBT-PEG polymers isalso known under a trade name POLYACTIVE and is available from IsoTisCorp. of Holland.

After the IPN-based outermost coating has been formed, it can besubjected to a post-coating treatment to cause blooming or migration ofthe hydrophilic component of the IPN to the coating-air interface. Forexample, any method of the post-coating treatment described above, orany combination thereof, can be used.

One kind of an IPN is a hydrogel. If it is desirable to include ahydrogel in the outermost layer of the stent coating, PBT-PEG can beused as a hydrogel-forming product. PBT-PEG can be utilized forfabricating not only the outermost layer (e.g., the topcoat layer) ofthe coating but for making all other layers of the stent-coating (e.g.,the primer layer or the drug-polymer layer) as well. In one embodiment,the stent coating can include only PBT-PEG and be free of any otherpolymers. The molecular weight of the PEG portion of the PBT-PEG polymercan be between about 300 and about 4,000 Daltons. In PBT-PEG polymer,the units derived from ethylene glycol (“the PEG units”) can constitutebetween about 40 and about 90 molar % of the total PBT-PEG polymer. Forexample, the PEG units can constitute between about 55 and about 80molar % of the total PBT-PEG polymer.

The active agent or a drug can include any substance capable of exertinga therapeutic or prophylactic effect in the practice of the presentinvention. The drug may include small molecule drugs, peptides,proteins, oligonucleotides, and the like. Examples of drugs includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof. Synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁. Theactive agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin, hydrochloride, and mitomycin.Examples of such antiplatelets, anticoagulants, antifibrin, andantithrombins include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogs, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, andthrombin. Examples of such cytostatic or antiproliferative agentsinclude angiopeptin, angiotensin converting enzyme inhibitors such ascaptopril, cilazapril or lisinopril, calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (ω-3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium.

Other therapeutic substances or agents which may be appropriate includealpha-interferon; genetically engineered epithelial cells; rapamycin andstructural derivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of everolimusavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,tacrolimus, and dexamethasone.

The coatings and methods of the present invention have been describedwith reference to a stent, such as a balloon expandable orself-expandable stent. The use of the coating is not limited to stents,however, and the coating can also be used with a variety of othermedical devices. Examples of the implantable medical device, that can beused in conjunction with the embodiments of this invention includestent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shuntsand endocardial leads (e.g., FINELINE and ENDOTAK, available fromGuidant Corporation). The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt-chromium alloys (e.g.,ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy,platinum, platinum-based alloys such as, e.g., platinum-iridium alloy,iridium, gold, magnesium, titanium, titanium-based alloys,zirconium-based alloys, or combinations thereof. Devices made frombioabsorbable or biostable polymers can also be used with theembodiments of the present invention.

“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co. ofJenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

Embodiments of the present invention can be further illustrated by thefollowing set forth examples.

EXAMPLE 1

A first composition can be prepared by mixing the following components:

-   -   (a) between about 1.0 mass % and about 15 mass %, for example,        about 2.0 mass % EVAL; and    -   (b) the balance, DMAC solvent.

The first composition can be applied onto the surface of a bare 13 mmTETRA stent (available from Guidant Corporation) by spraying and driedto form a primer layer. A spray coater can be used having a 0.014 fannozzle maintained at about 60° C. with a feed pressure of about 0.2 atm(about 3 psi) and an atomization pressure of about 1.3 atm (about 20psi). About 70 μg of the wet coating can be applied. The primer can bebaked at about 140° C. for about 2 hours, yielding a dry primer layer.

A second composition can be prepared by mixing the following components:

-   -   (a) between about 1.0 mass % and about 15 mass %, for example,        about 2.0 mass % EVAL;    -   (b) between about 0.05 mass % and about 2.0 mass %, for example,        about 1.0 mass % everolimus; and    -   (c) the balance, DMAC solvent.

The second composition can be applied onto the dried primer layer toform the reservoir layer, using the same spraying technique andequipment used for applying the primer layer. About 400 μg of the wetcoating can be applied, followed by drying, e.g., by baking as describedabove.

A third composition can be prepared by mixing the following components:

-   -   (a) between about 1.0 mass % and about 15 mass %, for example,        about 2.0 mass % EVAL;    -   (b) between about 0.5 mass % and about 5.0 mass %, for example,        about 1.0 mass % poly(ethylene glycol) having molecular weight        of about 17,500; and    -   (c) the balance, a solvent mixture comprising DMAC and ethanol        (EtOH) in a mass ratio DMAC:EtOH of about 4:1.

The third composition can be applied onto the dried reservoir layer toform a topcoat layer, using the same spraying technique and equipmentused for applying the primer layer and the reservoir layer. About 200 μgof the wet coating can be applied, followed by drying, e.g., by bakingas described above.

The coated stent can be placed in a humidifying chamber for about 24hours, at a temperature of about 50° C. and relative humidity of about100%, followed by removing the stent from the humidifying chamber anddrying.

EXAMPLE 2

The stent can be coated as described in Example 1, except when preparingthe composition for fabricating the topcoat layer, instead ofpoly(ethylene glycol) having molecular weight of about 17,500,poly(ethylene glycol)-stearate having molecular weight of about 4,000can be used.

The coated stent can be treated in the humidifying chamber as describedin Example 1.

EXAMPLE 3

The stent can be coated as described in Example 1. The coated stent canbe can be placed in a refrigerating unit and exposed to a temperature ofabout −10° C. for about 1 hour. Following the cooling process, the stentcan be dried in the ambient atmosphere for about 24 hours.

EXAMPLE 4

A first composition was prepared by mixing the following components:

-   -   (a) about 2.0 mass % PBT-PEG; and    -   (b) the balance, a solvent blend, the blend comprising        1,1,2-tricloroethane and chloroform in a mass ratio between        1,1,2-tricloroethane and chloroform of about 4:1.

The brand of PBT-PEG that was used had about 45 molar % units derivedfrom PBT and about 55 molar % units derived from PEG. The molecularweight of the PEG units was about 300 Daltons. The first composition wasapplied onto the surface of a bare 13 mm PENTA stent (available fromGuidant Corporation) by spraying and dried to form a primer layer. Theprimer was baked at about 140° C. for about 1 hour, yielding a dryprimer layer having solids content of about 100 μg. “Solids” means theamount of the dry residue deposited on the stent after all volatileorganic compounds (e.g., the solvent) have been removed.

A second composition was prepared by mixing the following components:

-   -   (a) about 2 mass % PBT-PEG;    -   (b) about 2 mass % everolimus; and    -   (c) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The same brand of PBT-PEG as that utilized for making the primer layerwas used. The second composition was applied onto the dried primer layerto form the reservoir layer. The second composition was baked at about50° C. for about 1 hour, yielding a dry reservoir layer having solidscontent of about 300 μg.

A third composition was prepared by mixing the following components:

-   -   (a) about 2.0 mass % PBT-PEG having about 20 molar % units        derived from PBT and about 80 molar % units derived from PEG.        The molecular weight of the PEG units was about 4,000 Daltons;        and    -   (b) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The third composition was applied onto the dried reservoir layer to forma topcoat layer. The third composition was baked at about 50° C. forabout 2 hours, yielding a dry topcoat layer having solids content ofabout 100 μg.

EXAMPLE 5

A stent was coated with a primer layer and a reservoir layer asdescribed in Example 4. A composition was prepared, comprising:

-   -   (a) about 1.0 mass % PBT-PEG having about 45 molar % units        derived from PBT and about 55 molar % units derived from PEG.        The molecular weight of the PEG units was about 300 Daltons;    -   (b) about 1.0 mass % PBT-PEG having about 20 molar % units        derived from PBT and about 80 molar % units derived from PEG.        The molecular weight of the PEG units was about 4,000 Daltons;        and    -   (c) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The composition was applied onto the dried reservoir layer and dried toform a topcoat layer, as described in Example 4. The topcoat layer hadsolids content of about 100 μg.

EXAMPLE 6

A stent was coated with a primer layer and a reservoir layer asdescribed in Example 4. A composition was prepared, comprising:

-   -   (a) about 1.0 mass % PBT-PEG having about 45 molar % units        derived from PBT and about 55 molar % units derived from PEG.        The molecular weight of the PEG units was about 300 Daltons;    -   (b) about 1.0 mass % PBT-PEG having about 40 molar % units        derived from PBT and about 60 molar % units derived from PEG.        The molecular weight of the PEG units was about 1,000 Daltons;        and    -   (c) the balance, 1,4-dioxane solvent.

The composition was applied onto the dried reservoir layer and dried toform a topcoat layer, as described in Example 4. The topcoat layer hadsolids content of about 100 μg.

EXAMPLE 7

A stent was coated with a primer layer described in Example 4. A firstcomposition was prepared by mixing the following components:

-   -   (a) about 2 mass % PBT-PEG;    -   (b) about 2 mass % paclitaxel; and    -   (c) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The same brand of PBT-PEG as that utilized for making the primer layerwas used. The first composition was applied onto the dried primer layerand dried to form a reservoir layer, as described in Example 4. Thereservoir layer had solids content of about 300 μg.

A second composition was prepared by mixing the following components:

-   -   (a) about 1.5 mass % PBT-PEG having about 45 molar % units        derived from PBT and about 55 molar % units derived from PEG.        The molecular weight of the PEG units was about 300 Daltons;    -   (b) about 0.5 mass % PBT-PEG having about 20 molar % units        derived from PBT and about 80 molar % units derived from PEG.        The molecular weight of the PEG units was about 4,000 Daltons;        and    -   (c) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The composition was applied onto the dried reservoir layer and dried toform a topcoat layer, as described in Example 4. The topcoat layer hadsolids content of about 100 μg.

EXAMPLE 8

A stent was coated with a primer layer and a reservoir layer asdescribed in Example 7. A composition was prepared, comprising:

-   -   (a) about mass 1.0% of PBT-PEG having about 45 molar % units        derived from PBT and about 55 molar % units derived from PEG.        The molecular weight of the PEG units was about 300 Daltons; and    -   (b) 1.0 about mass % PBT-PEG having about 20 molar % units        derived from PBT and about 80 molar % units derived from PEG.        The molecular weight of the PEG units was about 4,000 Daltons;    -   (c) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The composition was applied onto the dried reservoir layer and dried toform a topcoat layer, as described in Example 7. The topcoat layer hadsolids content of about 100 μg.

EXAMPLE 9

A 12 mm VISION stent (available from Guidant Corp.) was coated with aprimer layer described in Example 4. A first composition was prepared bymixing the following components:

-   -   (a) about 2 mass % everolimus; and    -   (b) the balance a the blend of acetone and xylene in a mass        ratio between acetone and xylene of about 2:3.

The first composition was applied onto the dried primer layer to formthe reservoir layer. The first composition was baked at about 50° C. forabout 1 hour, yielding a dry reservoir layer having solids content ofabout 200 μg.

A second composition was prepared, comprising:

-   -   (a) about 2.0 mass % of PBT-PEG having about 45 molar % units        derived from PBT and about 55 molar % units derived from PEG.        The molecular weight of the PEG units was about 300 Daltons; and    -   (b) the balance, the blend of 1,1,2-tricloroethane and        chloroform described above.

The second composition was applied onto the dried reservoir layer anddried to form a topcoat layer, as described in Example 4.

The coating compositions discussed in Examples 1-9 are summarized inTable 1.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention. TABLE 1 StentCoatings of Examples 1-9 Primer Reservoir Topcoat Example PolymerPolymer Drug Polymer 1 EVAL EVAL everolimus 1. EVAL 2. PEG (EVAL:PEGratio is 2:1) 2 EVAL EVAL everolimus 1. EVAL 2. PEG-stearate(EVAL:PEG-stearate ratio is 2:1) 3 EVAL EVAL everolimus 1. EVAL 2. PEG(EVAL:PEG ratio is 2:1) 4 PBT-PEG PBT-PEG everolimus PBT-PEG PBT - 45mol. % PBT - 45 mol. % PBT - 20 mol. %; PEG - 80 mol. % PEG - 55 mol. %PEG - 55 mol. % PEG's MW = 4,000 PEG's MW*⁾ = 300 PEG's MW = 300 5PBT-PEG PBT-PEG everolimus (1) PBT-PEG PBT - 45 mol. % PBT - 45 mol. %PBT - 45 mol. %; PEG - 55 mol. % PEG - 55 mol. % PEG - 55 mol. % PEG'sMW = 300 PEG's MW = 300 PEG's MW = 300 (2) PBT-PEG PBT - 20 mol. %;PEG - 80 mol. % PEG's MW = 4,000 Ratio (1) PBT-PEG:(2) PBT-PEG = 1:1 6PBT-PEG PBT-PEG everolimus (1) PBT-PEG PBT - 45 mol. % PBT - 45 mol. %PBT - 45 mol. %; PEG - 55 mol. % PEG - 55 mol. % PEG - 55 mol. % PEG'sMW = 300 PEG's MW = 300 PEG's MW = 300 (2) PBT-PEG PBT - 40 mol. %;PEG - 60 mol. % PEG's MW = 1,000 Ratio (1) PBT-PEG:(2) PBT-PEG = 1:1 7PBT-PEG PBT-PEG Paclitaxel (1) PBT-PEG PBT - 45 mol. % PBT - 45 mol. %PBT - 45 mol. %; PEG - 55 mol. % PEG - 55 mol. % PEG - 55 mol. % PEG'sMW = 300 PEG's MW = 300 PEG's MW = 300 (2) PBT-PEG PBT - 20 mol. %;PEG - 80 mol. % PEG's MW = 4,000 Ratio (1) PBT-PEG:(2) PBT-PEG = 3:1 8PBT-PEG PBT-PEG Paclitaxel (1) PBT-PEG PBT - 45 mol. % PBT - 45 mol. %PBT - 45 mol. %; PEG - 55 mol. % PEG - 55 mol. % PEG - 55 mol. % PEG'sMW = 300 PEG's MW = 300 PEG's MW = 300 (2) PBT-PEG PBT - 20 mol. %;PEG - 80 mol. % PEG's MW = 4,000 Ratio (1) PBT-PEG:(2) PBT-PEG = 1:1 9PBT-PEG N/A everolimus PBT-PEG PBT - 45 mol. % PBT - 45 mol. % PEG - 55mol. % PEG - 55 mol. % PEG's MW*⁾ = 300 PEG's MW*⁾ = 300*⁾MW is an abbreviation for “molecular weight”

1. A stent comprising a coating layer, the coating layer having ahydrophobic component and a hydrophilic component, wherein a region ofthe coating layer on or about the outermost surface of the coating layerhas a higher content or concentration of the hydrophilic component thanthe hydrophobic component and wherein the hydrophilic component has asolubility parameter higher than about 8.5 (cal/cm³)^(1/2).
 2. The stentof claim 1, wherein the hydrophobic and hydrophilic components areblended in the coating layer.
 3. The stent of claim 1, wherein thehydrophobic and hydrophilic components are bonded in the coating layer.4. The stent of claim 1, wherein the hydrophobic and hydrophiliccomponents are an interpenetrating polymer network.
 5. The stent ofclaim 1, wherein the solubility parameter is higher than about 9.0(cal/cm³)^(1/2).
 6. The stent of claim 1, wherein the solubilityparameter is higher than about 9.5 (cal/cm³)^(1/2).
 7. The stent ofclaim 1, wherein the solubility parameter is higher than about 10.0(cal/cm³)^(1/2).
 8. The stent of claim 1, wherein the solubilityparameter is higher than about 10.5 (cal/cm³)^(1/2).
 9. The stent ofclaim 1, wherein the solubility parameter is higher than about 11.0(cal/cm³)^(1/2).
 10. The stent of claim 1, wherein the solubilityparameter is higher than about 11.5 (cal/cm³)^(1/2).
 11. The stent ofclaim 1, wherein the hydrophobic component has a solubility parameterless than about 11.5 (cal/cm³)^(1/2).
 12. The stent of claim 1, whereinthe coating layer includes one or a combination of a primer layer, areservoir layer including a drug and a topcoat layer.
 13. The stent ofclaim 1, wherein the coating layer is the outermost layer of a coatingconstruct.
 14. The stent of claim 1, wherein the radio of thehydrophilic component to the hydrophobic component is between about1:100 and about 1:9.